Place of care and costs associated with acute episodes and remission in schizophrenia

BACKGROUND: Schizophrenia imposes significant economic burden on patients, families, caregivers, and society. To our knowledge, place of care and associated costs of acute schizophrenia episodes have not been well characterized. OBJECTIVE: To describe the care settings and costs associated with likely acute episodes and untreated remission periods among patients with schizophrenia. METHODS: Adults with schizophrenia were identified using the IBM MarketScan Commercial and Medicare Supplemental databases (2009-2018); claims for capitated benefits plans were excluded. Acute episode index date was defined as at least 1 inpatient schizophrenia claim or outpatient schizophrenia claim (frequency of claim dependent on visit type, such as hospitalization, emergency department, private practice, clinic, urgent care, or laboratory). Mental health–related medical costs (health plan+patient) associated with acute episodes were collected over a 2-month follow-up period and stratified by setting (inpatient vs outpatient); acute episode data were reported in subgroups of patients without or with prior clozapine use, as an indication of disease severity. Remission index date was defined as at least 1 outpatient claim with a schizophrenia diagnosis with no acute episode and no oral or injectable antipsychotic therapy. Remission costs were assessed over a 3-month period. All data were analyzed descriptively. RESULTS: A total of 14,824 patients with schizophrenia met criteria for an acute episode (12,896 [87.0%] without prior clozapine use; 1,427 [9.6%] with prior clozapine use). Most acute episodes were treated in an outpatient setting (all patients, 76.3%; without prior clozapine use, 74.5%; with prior clozapine use, 87.1%). When treated inpatient, mean (SD) episode medical costs were $17,045 ($28,101) for all patients, $16,060 ($22,786) for those without prior clozapine use, and $22,827 ($55,860) for those with prior clozapine use. When treated outpatient, mean (SD) medical costs for acute episodes were $2,478 ($6,961) for all patients, $2,609 ($7,068) for those without prior clozapine use, and $1,770 ($6,560) for those with prior clozapine use. For all patients with acute episodes, regardless of clozapine use, patient-incurred out-of-pocket costs were approximately 30% of total medical costs. For an untreated period of remission, 6,950 patients with schizophrenia met criteria. Total medical costs were $2,399 for these patients over a 3-month period. CONCLUSIONS: The majority of acute schizophrenia episodes were treated in the outpatient setting. For episodes that required inpatient care, inpatient episodes were approximately 7 times more costly than episodes treated in outpatient-only settings. For acute episodes and remission periods, health plans covered most costs; however, there were additional patient-incurred out-of-pocket costs.


Plain language summary
This study looked at the care setting and costs during acute schizophrenia episodes and periods with no symptoms. The results showed that episodes are mostly treated in outpatient settings. Inpatient costs were 7 times higher than outpatient costs. Pharmacy costs were lower than medical costs in both inpatient and outpatient settings. Health insurance plans covered most costs.

Implications for managed care pharmacy
In this claims-based study, we evaluated the place of care and associated costs of acute schizophrenia episodes and periods of remission. Although most acute episodes were managed in the outpatient setting, episodes with inpatient care were approximately 7 times more costly than outpatient-only episodes. Regardless of setting, pharmacy costs were considerably lower than medical costs. These findings should inform managed care policy by encouraging access to effective schizophrenia medications to potentially avoid costly inpatient services.
Place of care and costs associated with acute episodes and remission in schizophrenia psychosis that requires ED visits and subsequent hospitalizations, 19,20 particularly if they are exhibiting aggressive behavior or are at risk of harming themselves or others. 21,22 Gaps in antipsychotic medication use is also a predictor of inpatient admission. 23 Patients with a recent relapse (ie, within the previous 6 months) incur approximately 3 times greater annual direct mental health costs and significantly greater annual hospitalization costs following the relapse than patients without a recent relapse. 24 Overall rates of schizophrenia-related hospitalizations significantly increased from 2005 to 2014 in the United States despite decreases in the average length of stay. 25 Setting aside inflation as a contributing factor, authors hypothesized that the increase was due to poor medication adherence among younger patients with schizophrenia that led to more inpatient visits and subsequently higher inpatient costs.
Although it is known that there are considerable direct costs associated with schizophrenia, there are limited published data reporting the setting (inpatient vs outpatient) in which patients are treated for an acute episode and the associated costs. To address this knowledge gap, the objective of this study was to describe the place of care and estimate health-related costs associated with acute episodes, as well as untreated remission periods among patients with schizophrenia.

STUDY DESIGN
Adults (aged ≥ 18 years) with schizophrenia were identified using the IBM MarketScan Commercial and Medicare Supplemental databases (January 1, 2009, to December 31, 2018). The Commercial database included medical and pharmacy claims for more than 225 million patients from 300 contributing employers and 40 contributed health plans across the United States. The Medicare database contained enrollment and health care claims of 6.4 million retirees and people with disabilities with Medicare insurance. All included patients were continuously enrolled for at least 12 months prior to and 6 months after the index date. The study was divided into 2 cohorts: patients in an acute treatment phase (acute episodes) and patients in a stable, no treatment phase (remission).
To identify acute episodes of schizophrenia, a novel, claims-based approach was used. Guided by expert opinion, a combination of the following factors and criteria were determined to be suggestive of acute episodes: schizophrenia diagnosis codes (Supplementary Table 1, available in online article), place of service, and frequency of service within a short duration (2 weeks). An acute episode index Schizophrenia is a severe, chronic, and heterogenous psychiatric disorder that affects approximately 3.5 million people in the United States. 1 For most patients with schizophrenia, the course of illness is characterized by multiple episodes of relapse, 2 which can worsen long-term disease outcomes. 3 In addition, schizophrenia places significant economic burden on patients, families, caregivers, payers, and society. 4 In 2013, the annual health care costs associated with schizophrenia exceeded $155 billion in the United States alone. 5 Approximately one-quarter of these costs were attributed to direct health care costs, which included inpatient and outpatient services, emergency department (ED) visits, long-term care, medications, and other medical services. Inpatient services accounted for $15.2 billion of the total excess costs, which was over twice those of outpatient services ($7.4 billion). Moreover, patients with schizophrenia incur higher health care costs than those without schizophrenia. For example, in a study that compared the costs of care between Medicare beneficiaries with and without schizophrenia, those with schizophrenia had 80% higher per-patient-per-year costs. 6 In an analysis of commercially insured patients, the average total claim cost per patient with schizophrenia was over 4 times that of a demographically adjusted population without schizophrenia. 7 The clinical and economic consequences of relapse underscore the importance of achieving the long-term goals of schizophrenia management, which include remission and relapse prevention. 3 For both acute and maintenance treatment of schizophrenia, antipsychotic medications have demonstrated efficacy vs placebo and are considered the mainstay of treatment. [8][9][10] Per the American Psychiatric Association treatment guidelines, which recommend antipsychotic medication use as first-line treatment in patients with schizophrenia, 11 patients should be monitored for efficacy and side effects during antipsychotic use and should continue their medication if symptoms improve. Adverse effects (AEs) associated with antipsychotics include weight gain, 12 hyperprolactinemia (elevated prolactin levels), 13 metabolic changes, 14 and extrapyramidal symptoms. 8 Atypical antipsychotics are often preferred because they tend to cause fewer extrapyramidal symptoms than conventional, typical antipsychotics. 15,16 According to the American Psychiatric Association guidelines, 11 clozapine should be reserved for more severe illness, such as cases of treatment resistance or if the patient remains at substantial suicide risk despite other treatments 17 ; consequently, clozapine use is generally infrequent among patients with schizophrenia (< 5%) 18 and likely signals greater schizophrenia severity.
Inpatient services account for a substantial portion of the costs associated with schizophrenia care. During acute schizophrenia episodes, patients may experience active Place of care and costs associated with acute episodes and remission in schizophrenia plan+patient) and health plan-only payments. For analysis of pharmacy costs, the pharmacy was considered the provider. For acute episodes, cost outcomes were assessed for 2 mutually exclusive time periods: (1) acute episode (ie, duration of inpatient stay when treated in the inpatient setting or 2 weeks following in the initial outpatient claim when treated in the outpatient setting) and (2) 2-month follow-up, which began the day after discharge for inpatient acute episodes or after the 2 weeks following the first outpatient claim for outpatient acute episodes. Costs for these periods were stratified by setting of the acute episode (inpatient vs outpatient). For acute episodes, mental health-related pharmacy costs were additionally classified by the following medication subgroups: oral atypical antipsychotics, nonoral atypical antipsychotics, typical antipsychotics, and other mental health-related medications (excluding all antipsychotics). Multiple episodes per patient were included in the analysis. Additionally, for acute inpatient episodes, pharmacy costs observed between the dates of hospital admission and discharge were included in addition to the inpatient admission costs. Further, mental health-related costs were assessed during remission periods, which had a duration of 3 months. Demographics and baseline characteristics were assessed descriptively. Place of care and cost data described herein were analyzed descriptively and presented as mean mental health-related costs.

PATIENT SELECTION AND CHARACTERISTICS
A total of 14,824 patients with schizophrenia met the criteria for an acute episode, of whom 12,896 (87.0%) were included in the "without prior clozapine use" cohort and 1,427 (9.6%) in the "with prior clozapine use" cohort (Supplementary Figure 1). A total of 6,950 patients met the criteria for remission.
Demographics and baseline patient characteristics at index were generally similar across groups ( Table 1). The average age (in years) was early to middle 40s, and 54% of patients were male. More than 75% of patients had commercial insurance, and approximately 50% of patients were enrolled in preferred provider organization health plans.

ACUTE EPISODE CARE SETTINGS
The vast majority of acute schizophrenia episodes (approximately 75%) were treated in an outpatient setting, regardless of clozapine use ( Figure 1). For those episodes treated in an inpatient setting, the mean length of an inpatient stay when hospitalized was approximately 11 days for patients without date was defined as the first claim date in patients who met any of the following criteria: at least 1 inpatient schizophrenia claim or at least 1 outpatient claim at an urgent care facility, outpatient hospital (on campus), ED (hospital), skilled nursing facility, nursing facility, ambulance (land), or comprehensive inpatient or outpatient rehab facility or at least 3 outpatient claims on 3 distinct days within a 2-week period for services associated with pharmacy, telehealth, office, patient or group home, assisted living facility, outpatient hospital (off campus), custodial care facility, independent clinic, federally qualified health center, psychiatric facility partial hospitalization, community mental health center, intermediate care/intellectual disability, residential or nonresidential substance use facility, psychiatric residential treatment center, state/local public health clinic, rural health clinic, or outpatient (not elsewhere classified). A schizophrenia claim was defined as any claim with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) or ICD-10 code for schizophrenia in any position.
Patients in the acute treatment cohort were also required to have at least 1 inpatient or outpatient claim with a schizophrenia diagnosis in any position and at least 2 prescriptions for an oral atypical antipsychotic (ie, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, fluoxetine/olanzapine, iloperidone, lurasidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, or ziprasidone) in the baseline period. For acute episodes, the main cohort (all patients) was evaluated as well as subgroups of patients with or without prior clozapine use (defined as the presence of ≥ 2 prescriptions for clozapine in the baseline period on separate days), with clozapine use as an indication of greater disease severity.
The remission index date was defined as the first claim date in patients who had at least 1 outpatient claim with a schizophrenia remission diagnosis (ICD-9) or a schizophrenia stable, no treatment diagnosis (ICD-10) with no acute episode. Patients also could not have any oral or injectable antipsychotic therapy claims in the 6-month follow-up period (Supplementary Table 2). Patients in this remission cohort were also required to have at least 1 inpatient or outpatient claim with a schizophrenia diagnosis (excluding schizophreniform) in any position during the baseline period.

OUTCOMES AND ANALYSIS
Mental health-related medical and pharmacy costs, based on mental health-related ICD-9/10 codes, were assessed; only noncapitated costs were included in the analysis and were adjusted to 2019 USD values. Cost outcomes were reported both as total payment to providers (health Place of care and costs associated with acute episodes and remission in schizophrenia prior clozapine use and approximately 15 days for patients with prior clozapine use. Mean episodes per patient were approximately 3 for all patients, 2 for patients without prior clozapine use, and 5 for patients with prior clozapine use.

Place of care and costs associated with acute episodes and remission in schizophrenia
Total mental health-related pharmacy costs for all patients during the acute episode and follow-up period were $197 and $806, respectively ( Figure 4); costs were numerically similar between patients without and with prior clozapine use (Supplementary Figure 2). Oral atypical antipsychotic costs were between 60% and 70% of total pharmacy costs for all patients or patients without prior clozapine use and more than 70% of total pharmacy costs for patients with prior clozapine use. For all patients, regardless of clozapine use, health plans covered more than 85% of pharmacy costs. The percentage of patient-incurred out-of-pocket total pharmacy costs was approximately 12% during both acute episodes and follow-up.

COSTS DURING REMISSION
The 3-month outpatient mental health-related total costs for patients with an untreated period of remission were $2,501 and health plan-only costs were $1,602 (Supplementary Figure 3). The bulk of these mental health-related costs (≥95%) were for medical visits.  Place of care and costs associated with acute episodes and remission in schizophrenia treated in an outpatient setting. Regardless of setting, mental health-related pharmacy costs associated with acute episodes were considerably lower than medical costs. The majority of pharmacy costs were for oral atypical antipsychotics, which would be expected because they are the primary treatment prescribed to patients with schizophrenia. During periods of remission, medical visits accounted for the majority of 3-month outpatient mental health-related costs. Health plans covered most medical and pharmacy costs both for acute episodes and for untreated periods of remission; however, patients also incurred out-of-pocket costs, which were approximately 30% of total medical costs and 12% of total pharmacy costs for patients with acute episodes. Schizophrenia is associated with high rates of relapse, particularly following hospitalizations. For example, schizophrenia and other psychotic disorders are the leading cause of 7-day readmission and the second leading cause

Discussion
Schizophrenia, a serious chronic mental health disorder, is associated with substantial health care costs and resource utilization. To our knowledge, this study is the first to estimate costs and care settings (inpatient or outpatient) associated with acute schizophrenia episodes, updating our understanding of the location of care and its associated costs. Using a novel, claims-based methodological approach, we analyzed claims data to define acute schizophrenia episodes. Key factors (eg, type of code, frequency, and time period) were intentionally selected to identify likely acute episodes.
Overall, the majority of acute episodes (approximately 75%) in adults with schizophrenia were treated in the outpatient setting. Interestingly, approximately 90% of acute episodes in patients with prior clozapine use, which represented a more likely severe disease state, were  Place of care and costs associated with acute episodes and remission in schizophrenia been associated with increased use of emergency psychiatric services, hospitalizations, and higher inpatient care costs. 24,31 In cases of partial adherence, medications with longer half-lives may prolong drug exposure, which can bridge gaps in medication intake. Nonadherence in schizophrenia is also multidimensional and can vary between patients, but the AEs associated with antipsychotic treatment are a potential barrier to adherence. 32, 33 Particularly distressing AEs that may contribute to nonadherence include sexual dysfunction due to hyperprolactinemia 34 and weight gain. 35 Given these issues, newer antipsychotic medications with better tolerability profiles may improve adherence and potentially reduce the significant costs associated with inpatient care. Future research is needed to identify effective strategies to reduce schizophrenia-related hospitalizations and minimize costly inpatient services.

LIMITATIONS
The methods used for defining likely acute schizophrenia episodes represent a new approach that may overcome some of the methodological challenges associated with using claims data, which provide valuable information for evaluating care settings and costs. However, there are inherent limitations associated with claims database analyses, and the results of this study should be interpreted within these limitations. As with all claims data, there was potential for data coding and/or entry errors. Analysis was limited to individuals with commercial or Medicare coverage, and outof-network treatments for schizophrenia or capitated costs were not captured. Therefore, the results may not be generalizable to patients with other insurance (eg, Medicaid), no insurance coverage, or patients in fully capitated health plans. A minimum coverage period was required, which may have contributed to selection bias. Further, the claims database analysis did not include baseline comorbid conditions or adherence rates, both of which could contribute to patients being treated inpatient vs outpatient. In addition, episode and remission costs cannot be compared directly given the different follow-up periods (ie, 2 months vs 3 months). Acute episodes and untreated periods of remission were both identified using proxy criteria based on claims data via a novel algorithm that is not yet validated. Psychiatric diagnosis and visits were used as proxies for acute schizophrenia episodes, but we could not be certain that these patients actually experienced an acute episode. In addition, the ICD-10 lacks a code for remission so the "stable, no treatment" code was used, and the ICD-9 schizophrenia remission code may be infrequently used. Therefore, we can only assume that untreated periods of remission were adequately captured. Although both sets of proxy criteria were discussed with and approved by all of 30-day readmission after an initial hospital stay. 26 Given this high likelihood of schizophrenia relapse, the relatively long follow-up period (2 months in duration) used in this study was designed to capture the full extent of costs of care associated with acute schizophrenia episodes. Results indicated that, in both inpatient and outpatient settings, the service costs for managing acute episodes were distributed throughout the follow-up period. Approximately half of the total costs of each inpatient episode were incurred during the 2-month follow-up period after an inpatient stay, which suggests that calculating event costs only during inpatient hospitalization could underestimate true episodic costs by approximately 50%. In addition, follow-up outpatient costs were greater than costs incurred during the acute episode (ie, 2-week period after the first outpatient claim) for all patients, regardless of clozapine use. These results suggest that the costs and utilization of services associated with acute schizophrenia episodes are incurred over an extended period of time, regardless of the place of care. Therefore, study designs that exclude or use a shorter follow-up period may substantially underestimate the costs associated with acute schizophrenia episodes, especially for outpatient care. These findings may be relevant to future policy assessments, such as cost-effectiveness analysis modeling; in future studies, researchers should accurately reflect the place of service (inpatient vs outpatient) and account for follow-up costs to fully capture the true impact of schizophrenia relapse.
Inpatient care services represent a considerable portion of the economic burden of schizophrenia in the United States. For example, Fitch et al reported that inpatient resources accounted for more than 40% of the per-patient-per-month costs in patients newly diagnosed with schizophrenia and that these costs were highest during the month following diagnosis, primarily because of high costs associated with inpatient care. 7 Similarly, in a study of Medicare beneficiaries with schizophrenia, more than half of the per-patient-per-year costs were attributed to psychiatric and medical hospitalizations, which occurred in approximately 30% of those with schizophrenia 6 In this study, mental health-related inpatient costs were approximately 7 times greater than outpatient costs among patients who required inpatient care for acute schizophrenia episodes.
One potential strategy for decreasing costly inpatient services is to reduce medication nonadherence and partial adherence, 23,27 which threaten symptomatic stability and functioning 28 and have been shown to be a predictor of hospitalization. 23 It has been estimated that approximately half of patients with schizophrenia are treatment-nonadherent to some degree. 29, 30 Further, treatment nonadherence has Place of care and costs associated with acute episodes and remission in schizophrenia investigators prior to the start of the study, it is possible that the criteria did not capture the full nature of schizophrenia episodes and remission. Further, length of diagnosis was not considered in the analysis, a factor which could have impacted outcomes. Finally, the relatively small number of patients with prior clozapine use (approximately 10% of all patients) should be noted as a potential limitation. Because adjusted analyses were not performed, comparisons between the cohorts (ie, without prior clozapine use vs with prior clozapine use) should be interpreted with caution.

Conclusions
The results of this study indicate that most acute schizophrenia episodes are treated in the outpatient setting. Although episodes that required inpatient care were less frequent, inpatient costs were approximately 7 times higher than outpatient costs. Pharmacy costs were considerably lower than medical costs, regardless of setting. Although health plans covered the majority of medical and pharmacy costs, there were additional patient-incurred out-of-pocket costs. This study is the first to estimate costs and setting of acute schizophrenia episodes, advancing our understanding of the location of schizophrenia care and the associated costs to the health care system.